WDR-5 Inhibits DAF-16 Activity And Shortens Caenorhabditis Elegans Lifespan By The Interaction With PRMT-1

Organism's aging is generally thought to be a time-dependent functional decline.The occurrence of various human diseases is related to the aging process.However,with the past 30 years of research,especially since researchers have discovered that single gene mutations can cause changes in the life span of C.elegans,fruit flies and other organisms,it is recognized that the senescence of organisms is regulated by gene expression.Epigenetic modification is one of the important ways to regulate gene expression.In recent years,more and more evidence shows that epigenetic modifications play an important role in the regulation of aging.Epigenetic modifications include DNA methylation,chromatin modification,and histone modification.Histone methylation is an important histone modification that occurs mainly in the lysines K4,K9,K27 and K36 of histone H3.Methylation at the above sites has been shown to correlate with the regulation of the aging process.WDR-5 is an important member of the histone H3K4me3 complex.Studies reported that the complex induction of senescence in C.elegans by histone H3K4me3 modification.The deletion of members wdr-5,set-2 and ash-2 in this complex all resulted in an extension of the lifespan of the nematode.However,the absence of wdr-5 did not completely inhibit the prolongation of the lifespan of nematodes by the set-2 and ash-2 mutations.This suggests that WDR-5 may interact with other enzymes in addition to its role in regulating the lifespan of H3K4me3 regulatory complexes.It is known that the asymmetric dimethylation of histone H3 arginine at the second position(H3R2me2a)inhibits the binding of WDR-5 to histone H3.Since PRMT-1 is the only enzyme responsible for catalyzing the modification of H3R2me2 a.Moreover,it has been reported that PRMT-1 promotes DAF-16 entry into the nucleus and inhibits nematode senescence through the methylation transcription factor DAF-16.Therefore,we speculate that the role of WDR-5 in promoting senescence in nematodes may be related to PRMT-1.To prove this problem,we first studied wild type of C.elegans,wdr-5(ok1417)and prmt-1(ok2170)mutants,and wdr-5(ok1417);prmt-1(ok2170)double mutants.Life-span testing showed that WDR-5 regulates nematode life indeed and PRMT-1.Next,we use GST-pulldown technology to prove that WDR-5 and PRMT-1 are integrated with each other.Using the wdr-5(ok1417);daf-16(mu86)double mutant,we further found that WDR-5 regulates the lifespan of nematodes associated with DAF-16.On the other hand,laser confocal and RT-qPCR results showed that WDR-5 can inhibit the entry of DAF-16 into the nucleus and reduce the mRNA expression level of DAF-16 target gene.Moreover,this inhibition depends on PRMT-1.Finally,we found that WDR-5 inhibited the binding of PRMT-1 to DAF-16 by co-IP(co-immunoprecipitation)experiments.The above results indicate that WDR-5 not only relies on the histone H3K4me3 complex but also promotes nematode senescence through PRMT-1.WDR-5 inhibits the interaction between PRMT-1 and DAF-16 by binding to PRMT-1,thereby preventing the entry of DAF-16 into the nucleus and reducing the expression level of DAF-16 target gene,leading to senescence of nematodes.This discovery will provide a new molecular mechanism for WDR-5 regulation of nematode aging,adding new content to the epigenetic regulation of aging.